Tau pathology, microglia activation, and network dysfunction in Alzheimer’s disease

Tau pathology and neuroinflammation are key etio-pathogenetic mediators of Alzheimer’s disease (AD). Network dysfunction has also been reported in AD and linked to cognitive impairment. However, it is unclear how tau pathology and neuroinflammation contribute to network dysfunction and cognitive deficit in AD. I study these issues by combining: 1) positron emission tomography imaging using the [18F-AV]-1451 tracer (measuring in vivo tau pathology) or [11C]PK11195 ligand (indexing in vivo neuroinflammation), with 2) connectivity measures of resting-state functional magnetic resonance imaging. I found increased [18F-AV]-1451 binding (reflecting tau pathology) in AD patients, relative to controls, in the medial/lateral temporal and parietal cortices. In terms of functional connectivity, more strongly connected brain regions accrued more tau pathology. Increasing tau burden was also linked to progressive weakening of the connectivity across the same regions. I also found increased [11C]PK11195 binding (reflecting neuroinflammation) in the medial/lateral temporal and parietal cortices in AD patients, relative to controls. [11C]PK11195 binding in the cuneus/precuneus correlated with episodic memory deficits in AD patients. This pattern of neuroinflammation was linked to large-scale network’ dysfunction and cognitive deficit. AD patients with enhanced neuroinflammation showed more abnormal connectivity across the whole-brain. The expression of a stronger association between altered functional connectivity and high levels of neuroinflammation related to cognitive deficit in AD. My studies have wide-ranging implications that include: 1) the validation of animal models of tau propagation in living patients with AD; 2) improvements in our understanding of the relationship between in vivo tau pathology and brain functioning; 3) evidence for a primary role of neuroinflammation in mediating network dysfunction in AD; 4) support to the notion that immune-therapeutic strategies targeting tau pathology and neuroinflammation may be useful in AD.MRC and NIHR funde

Persistent postural-perceptual dizziness: a useful new syndrome.

In this issue of Practical Neurology, Popkirov, Staab and Stone illuminate a newly defined condition—persistent postural-perceptual dizziness or ‘PPPD’, a maladaptive functional syndrome in which patients feel unbalanced despite not falling, and feel that they are moving, despite being stationary. PPPD is common in specialist dizzy clinics, accounting for 10% of cases as a primary diagnosis of dizziness. PPPD can coexist with other causes of dizziness, such as vestibular migraine or benign paroxysmal positional vertigo, and it is in this form that it most commonly presents to a specialist dizzy clinic.BMS: funded by the Medical Research Council, the NIHR Imperial Biomedical Research Centre, and the Imperial Health Charity. LP: funded by the Medical Research Council (MRC) (MR/P01271X/1) at the University of Cambridge, UK

Sleep quality relates to emotional reactivity via intracortical myelination

A good quality and amount of sleep are fundamental to preserve cognition and affect. New evidence also indicates that poor sleep is detrimental for brain myelination. In this study, we test the hypothesis that sleep quality and/or quantity relate to variability in cognitive and emotional function via the mediating effect of inter-individuals differences in proxy neuroimaging measures of white-matter integrity and intra-cortical myelination. By employing a demographically and neuropsychologically well-characterized sample of healthy people drawn from the Human Connectome Project (n=974), we found that quality and amount of sleep were only marginally linked to cognitive performance. In contrast, poor quality and short sleep increased negative affect (i.e., anger, fear, and perceived stress) and reduced life satisfaction and positive emotionality. At the brain level, poorer sleep quality and shorter sleep duration related to lower intra-cortical myelin in the mid-posterior cingulate cortex (p=0.038), middle temporal cortex (p=0.024), and anterior orbitofrontal cortex (OFC, p=0.034) but did not significantly affect different measures of white-matter integrity. Finally, lower intra-cortical myelin in the OFC mediated the association between poor sleep quality and negative emotionality (p<0.05). We conclude that intra-cortical myelination is an important mediator of the negative consequences of poor sleep on affective behaviour

Surface-based morphometry reveals the neuroanatomical basis of the five-factor model of personality.

The five-factor model (FFM) is a widely used taxonomy of human personality; yet its neuro anatomical basis remains unclear. This is partly because past associations between gray-matter volume and FFM were driven by different surface-based morphometry (SBM) indices (i.e. cortical thickness, surface area, cortical folding or any combination of them). To overcome this limitation, we used Free-Surfer to study how variability in SBM measures was related to the FFM in n = 507 participants from the Human Connectome Project.Neuroticism was associated with thicker cortex and smaller area and folding in prefrontal-temporal regions. Extraversion was linked to thicker pre-cuneus and smaller superior temporal cortex area. Openness was linked to thinner cortex and greater area and folding in prefrontal-parietal regions. Agreeableness was correlated to thinner prefrontal cortex and smaller fusiform gyrus area. Conscientiousness was associated with thicker cortex and smaller area and folding in prefrontal regions. These findings demonstrate that anatomical variability in prefrontal cortices is linked to individual differences in the socio-cognitive dispositions described by the FFM. Cortical thickness and surface area/folding were inversely related each others as a function of different FFM traits (neuroticism, extraversion and consciousness vs openness), which may reflect brain maturational effects that predispose or protect against psychiatric disorders.R.R. was funded by the University ‘Magna Graecia’ of Catanzaro, while L.P. was funded by the Italian National Research Council and the University of Cambridge. AT was funded by the National Institute on Aging (NIA), National Institutes of Health (NIH; 1R03AG051960-01) and by the Florida Department of Health ‘Ed and Ethel Moore Alzheimer’s Disease Research Program’ (6AZ09). Data were provided by the Human Connectome Project, WU-Minn Consortium (Principal Investigators: David Van Essen and Kamil Ugurbil; 1U54MH091657) funded by the 16 NIH Institutes and Centers that support the NIH Blueprint for Neuroscience Research; and by the McDonnell Center for Systems Neuroscience at Washington University. Data collection and sharing for this project was provided by the MGHUSC Human Connectome Project (HCP; Principal Investigators: Bruce Rosen, M.D., Ph.D., Arthur W. Toga, Ph.D., Van J. Weeden, MD). The HCP project is supported by the National Institute of Dental and Craniofacial Research (NIDCR), the National Institute of Mental Health (NIMH), and the National Institute of Neurological Disorders and Stroke (NINDS) (Principal Investigators: Bruce Rosen, M.D., Ph.D., Martinos Center at Massachusetts General Hospital; Arthur W. Toga, Ph.D., University of Southern California, Van J. Weeden, MD, Martinos Center at Massachusetts General Hospital). HCP is also the result of efforts of co-investigators from the University of Southern California, Martinos Center for Biomedical Imaging at Massachusetts General Hospital (MGH), Washington University, and the University of Minnesota

Co‐occurrence of apathy and impulsivity in progressive supranuclear palsy

Background: Apathy and impulsivity are common consequences of progressive supranuclear palsy (PSP) and can worsen its prognosis. They can co-exist in the same patients although their concomitant prevalence remains unclear. Their relationship to emotional lability is also unknown. Objectives: To estimate the co-occurrence of apathy and impulsivity and their relationship to emotional lability in PSP. To characterize the demographic, clinical, and cognitive features of PSP patients with apathy and impulsivity. Methods: In a retrospective study of a long-term clinical cohort, we assessed the prevalence of apathy, impulsivity, and emotional lability from clinical interviews, medical records, and contemporary carer questionnaires. 154 patients with a diagnosis of probable or possible PSP (according to the 2017 Movement Disorder Society criteria) were identified. 64 of these patients had neuropathological confirmation of PSP. PSP patients with both apathy and impulsivity were compared in terms of demographic, clinical, and cognitive characteristics to PSP patients with either one or neither of these neuropsychiatric features. Results: Apathy and impulsivity co-existed in two-thirds of people with PSP. A fifth displayed emotional lability in addition to apathy and impulsivity. Apathy and impulsivity were more commonly co-expressed than by chance. There was no single demographic, clinical or cognitive feature that distinguished between PSP patients with versus without apathy and impulsivity. Conclusions: The co-existence of apathy and impulsivity in PSP suggests that these neuropsychiatric features may share similar risk factors and etio-pathogenetic mechanisms. Apathy and impulsivity should be jointly assessed when planning symptomatic treatments for detrimental behavioural problems caused by PSP.This study was co-funded by the Cambridge University Centre for Parkinson-Plus (RG95450) and the Medical Research Council (RG91365). The Cambridge Brain Bank is supported by the NIHR Cambridge Biomedical Research Centre. The authors also declare that there are no conflicts of interest relevant to this wor

Brain Correlates of Persistent Postural-Perceptual Dizziness: A Review of Neuroimaging Studies.

Persistent postural-perceptual dizziness (PPPD), defined in 2017, is a vestibular disorder characterized by chronic dizziness that is exacerbated by upright posture and exposure to complex visual stimuli. This review focused on recent neuroimaging studies that explored the pathophysiological mechanisms underlying PPPD and three conditions that predated it. The emerging picture is that local activity and functional connectivity in multimodal vestibular cortical areas are decreased in PPPD, which is potentially related to structural abnormalities (e.g., reductions in cortical folding and grey-matter volume). Additionally, connectivity between the prefrontal cortex, which regulates attentional and emotional responses, and primary visual and motor regions appears to be increased in PPPD. These results complement physiological and psychological data identifying hypervigilant postural control and visual dependence in patients with PPPD, supporting the hypothesis that PPPD arises from shifts in interactions among visuo-vestibular, sensorimotor, and emotional networks that overweigh visual over vestibular inputs and increase the effects of anxiety-related mechanisms on locomotor control and spatial orientation

Heritability of human "directed" functional connectome

IntroductionThe functional connectivity patterns in the brain are highly heritable; however, it is unclear how genetic factors influence the directionality of such "information flows." Studying the "directionality" of the brain functional connectivity and assessing how heritability modulates it can improve our understanding of the human connectome. MethodsHere, we investigated the heritability of "directed" functional connections using a state-space formulation of Granger causality (GC), in conjunction with blind deconvolution methods accounting for local variability in the hemodynamic response function. Such GC implementation is ideal to explore the directionality of functional interactions across a large number of networks. Resting-state functional magnetic resonance imaging data were drawn from the Human Connectome Project (total n = 898 participants). To add robustness to our findings, the dataset was randomly split into a "discovery" and a "replication" sample (each with n = 449 participants). The two cohorts were carefully matched in terms of demographic variables and other confounding factors (e.g., education). The effect of shared environment was also modeled. ResultsThe parieto- and prefronto-cerebellar, parieto-prefrontal, and posterior-cingulate to hippocampus connections showed the highest and most replicable heritability effects with little influence by shared environment. In contrast, shared environmental factors significantly affected the visuo-parietal and sensory-motor directed connectivity. ConclusionWe suggest a robust role of heritability in influencing the directed connectivity of some cortico-subcortical circuits implicated in cognition. Further studies, for example using task-based fMRI and GC, are warranted to confirm the asymmetric effects of genetic factors on the functional connectivity within cognitive networks and their role in supporting executive functions and learning

Cortical thickness, surface area, and folding alterations in male youths with conduct disorder and varying levels of callous-unemotional traits

Purpose: previous studies have reported changes in gray matter volume in youths with conduct disorder (CD), although these differences are difficult to interpret as they may have been driven by alterations in cortical thickness, surface area (SA), or folding. The objective of this study was to use surface-based morphometry (SBM) methods to compare male youths with CD and age and sex-matched healthy controls (HCs) in cortical thickness, SA, and folding. We also tested for structural differences between the childhood-onset and adolescence-onset subtypes of CD and performed regression analyses to assess for relationships between CD symptoms and callous-unemotional (CU) traits and SBM-derived measures. Methods: we acquired structural neuroimaging data from 20 HC and 36 CD participants (18 with childhood-onset CD and 18 with adolescence-onset CD) and analysed the data using FreeSurfer. Results: relative to HCs, youths with CD showed reduced cortical thickness in the superior temporal gyrus, reduced SA in the orbitofrontal cortex (OFC), and increased cortical folding in the insula. There were no significant differences between the childhood-onset and adolescence-onset CD subgroups in cortical thickness or SA, but several frontal and temporal regions showed increased cortical folding in childhood-onset relative to adolescence-onset CD participants. CD symptoms were negatively correlated with OFC SA whereas CU traits were positively correlated with insula folding.Conclusions: cortical thinning in the superior temporal gyrus may contribute to the social cognitive impairments displayed by youths with CD, whereas reduced OFC SA may lead to impairments in emotion regulation and reward processing in youths with CD. The increased cortical folding observed in the insula may reflect a maturational delay in this region and could mediate the link between CU traits and empathy deficits. Altered cortical structure was observed in childhood-onset and adolescence-onset forms of C

Cortical thickness, surface area, and folding alterations in male youths with conduct disorder and varying levels of callous-unemotional traits.

PURPOSE: Previous studies have reported changes in gray matter volume in youths with conduct disorder (CD), although these differences are difficult to interpret as they may have been driven by alterations in cortical thickness, surface area (SA), or folding. The objective of this study was to use surface-based morphometry (SBM) methods to compare male youths with CD and age and sex-matched healthy controls (HCs) in cortical thickness, SA, and folding. We also tested for structural differences between the childhood-onset and adolescence-onset subtypes of CD and performed regression analyses to assess for relationships between CD symptoms and callous-unemotional (CU) traits and SBM-derived measures. METHODS: We acquired structural neuroimaging data from 20 HCs and 36 CD participants (18 with childhood-onset CD and 18 with adolescence-onset CD) and analyzed the data using FreeSurfer. RESULTS: Relative to HCs, youths with CD showed reduced cortical thickness in the superior temporal gyrus, reduced SA in the orbitofrontal cortex (OFC), and increased cortical folding in the insula. There were no significant differences between the childhood-onset and adolescence-onset CD subgroups in cortical thickness or SA, but several frontal and temporal regions showed increased cortical folding in childhood-onset relative to adolescence-onset CD participants. Both CD subgroups also showed increased cortical folding relative to HCs. CD symptoms were negatively correlated with OFC SA whereas CU traits were positively correlated with insula folding. CONCLUSIONS: Cortical thinning in the superior temporal gyrus may contribute to the social cognitive impairments displayed by youths with CD, whereas reduced OFC SA may lead to impairments in emotion regulation and reward processing in youths with CD. The increased cortical folding observed in the insula may reflect a maturational delay in this region and could mediate the link between CU traits and empathy deficits. Altered cortical folding was observed in childhood-onset and adolescence-onset forms of CD.This study was supported by Wellcome Trust project grant 083140 (Drs. Goodyer and Fairchild), Medical Research Council project code MC_US_A060_5PQ50 (Dr. Calder), and the Betty Behrens Research Fellowship at Clare Hall, Cambridge University (Dr. Passamonti). The authorswould like to thank the participants and their families for taking part in this study, as well as the Cambridge Youth Offending Service for their help with recruitment.This is the final version. It was first published by Elsevier at http://www.sciencedirect.com/science/article/pii/S2213158215000856

Multimodal and multicontrast image fusion via deep generative models

Recently, it has become progressively more evident that classic diagnostic labels are unable to reliably describe the complexity and variability of several clinical phenotypes. This is particularly true for a broad range of neuropsychiatric illnesses (e.g., depression, anxiety disorders, behavioral phenotypes). Patient heterogeneity can be better described by grouping individuals into novel categories based on empirically derived sections of intersecting continua that span across and beyond traditional categorical borders. In this context, neuroimaging data carry a wealth of spatiotemporally resolved information about each patient's brain. However, they are usually heavily collapsed a priori through procedures which are not learned as part of model training, and consequently not optimized for the downstream prediction task. This is because every individual participant usually comes with multiple whole-brain 3D imaging modalities often accompanied by a deep genotypic and phenotypic characterization, hence posing formidable computational challenges. In this paper we design a deep learning architecture based on generative models rooted in a modular approach and separable convolutional blocks to a) fuse multiple 3D neuroimaging modalities on a voxel-wise level, b) convert them into informative latent embeddings through heavy dimensionality reduction, c) maintain good generalizability and minimal information loss. As proof of concept, we test our architecture on the well characterized Human Connectome Project database demonstrating that our latent embeddings can be clustered into easily separable subject strata which, in turn, map to different phenotypical information which was not included in the embedding creation process. This may be of aid in predicting disease evolution as well as drug response, hence supporting mechanistic disease understanding and empowering clinical trials